Research: This proposal focuses on studying the molecular pathogenesis of human pituitary adenomas. Clonal origin of pituitary adenomas will be studied in patients with acromegaly, prolactinomas, Cushing's Disease and non-secretory tumors using x-chromosomal inactivation analysis. Both hypothalamic and pituitary abnormalities have been implicated in the pathogenesis of these common intracranial tumors. Monoclonality would favor a de novo intrinsic pituitary cell abnormality whereas polyclonality would indicate extrinsic hypothalamic growth-promoting factors. As many pituitary adenomas secrete two or more hormones, immunohistochemical studies will be performed to investigate whether these hormones are being produced by a single cell or separate cells in the same tumors and this information will be compared with the clonality of each tumor type. Preliminary data presented suggests that pituitary adenomas are monoclonal i.e. arise from a single mutated cell. This intrinsic pituitary cell mutation may be initiated or sustained by inactivation or loss of tumor suppressor genes. Therefore, chromosomal regions containing recessive mutations involving tumor suppressor genes will also be identified using known polymorphic sites in variable numbers of tandem repeats. Candidate: The P.I. has a sound clinical training in endocrinology and has recently acquired skills in molecular techniques in order to pursue a career in academic endocrinology as a physician scientist. The environment: The applicant will perform the research in the well-equipped laboratories of the sponsor and will be exposed to faculty experts in areas of pituitary gene expression and regulation, and will also be exposed to research in other areas of Endocrinology including bone and mineral metabolism, growth factor gene expression, insulin action, placental proteins and thyroid tumorigenesis. The applicant has access to sufficient human pituitary tissue to make this proposal feasible. Significance: This project will provide information on the pathogenesis of pituitary adenomas and also provide insight into etiology of reproductive dysfunction, growth abnormalities and metabolic dysfunction. This award will therefore afford the candidate an opportunity to develop her career as an independent clinical investigator.